A Facile Protocol for C(sp²)-C(sp³) Bond Formation Reactions Toward Functionalized E3 Ligase Ligands.

ABSTRACT: A straightforward method for creating C(sp²)-C(sp³) bonds is employed to develop novel cereblon (CRBN) E3 ligase ligands, essential for targeted protein degradation (TPD) applications. While most prior studies focus on biological activities, this work explores how the linker attachment and bond types affect physicochemical stability, binding affinity, and degrading performance. Utilizing N-hydroxyphthalimide (NHP) esters and aryl bromides, a resilient decarboxylative cross-coupling technique that broadens the available chemical space beyond traditional C(sp²)-N connections is developed. Several well-established and underexplored CRBN binders and their derivatives are synthesized and studied. Binding affinity, aqueous solubility, stability in microsomes, and

SUBMITTER: Maksutova A 

PROVIDER: S-EPMC12913232 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature